TY - JOUR
T1 - Tumor-derived prostaglandin E2 promotes p50 NF-kB-dependent differentiation of monocytic MDSCs
AU - Porta, Chiara
AU - Consonni, Francesca Maria
AU - Morlacchi, Sara
AU - Sangaletti, Sabina
AU - Bleve, Augusto
AU - Totaro, Maria Grazia
AU - Larghi, Paola
AU - Rimoldi, Monica
AU - Tripodo, Claudio
AU - Strauss, Laura
AU - Banfi, Stefania
AU - Storto, Mariangela
AU - Pressiani, Tiziana
AU - Rimassa, Lorenza
AU - Tartari, Silvia
AU - Ippolito, Alessandro
AU - Doni, Andrea
AU - Solda, Giulia
AU - Duga, Stefano
AU - Piccolo, Viviana
AU - Ostuni, Renato
AU - Natoli, Gioacchino
AU - Bronte, Vincenzo
AU - Balzac, Fiorella
AU - Turco, Emilia
AU - Hirsch, Emilio
AU - Colombo, Mario P.
AU - Sica, Antonio
N1 - Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and to hinder the effectiveness of anticancer treatments. Of note, in response to IFNg, M-MDSCs release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express antitumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-kB in M-MDSCs, diverting their response to IFNg toward NO-mediated immunosuppression and reducing TNFa expression. At the genome level, p50 NF-kB promoted binding of STAT1 to regulatory regions of selected IFNg-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacologic inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSCs toward a NOS2low/TNFahigh phenotype, restoring the in vivo antitumor activity of IFNg. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy.
AB - Myeloid-derived suppressor cells (MDSC) include immature monocytic (M-MDSC) and granulocytic (PMN-MDSC) cells that share the ability to suppress adaptive immunity and to hinder the effectiveness of anticancer treatments. Of note, in response to IFNg, M-MDSCs release the tumor-promoting and immunosuppressive molecule nitric oxide (NO), whereas macrophages largely express antitumor properties. Investigating these opposing activities, we found that tumor-derived prostaglandin E2 (PGE2) induces nuclear accumulation of p50 NF-kB in M-MDSCs, diverting their response to IFNg toward NO-mediated immunosuppression and reducing TNFa expression. At the genome level, p50 NF-kB promoted binding of STAT1 to regulatory regions of selected IFNg-dependent genes, including inducible nitric oxide synthase (Nos2). In agreement, ablation of p50 as well as pharmacologic inhibition of either the PGE2 receptor EP2 or NO production reprogrammed M-MDSCs toward a NOS2low/TNFahigh phenotype, restoring the in vivo antitumor activity of IFNg. Our results indicate that inhibition of the PGE2/p50/NO axis prevents MDSC-suppressive functions and restores the efficacy of anticancer immunotherapy.
UR - https://www.scopus.com/pages/publications/85087472010
U2 - 10.1158/0008-5472.CAN-19-2843
DO - 10.1158/0008-5472.CAN-19-2843
M3 - Article
SN - 0008-5472
VL - 80
SP - 2874
EP - 2888
JO - Cancer Research
JF - Cancer Research
IS - 13
ER -
